CARVEDILOL-LIPOSOME INTERACTION - EVIDENCE FOR STRONG ASSOCIATION WITH THE HYDROPHOBIC REGION OF THE LIPID BILAYERS

Carvedilol (Kredex, Coreg) is a multiple action antihypertensive drug that has been shown to protect cell membranes from lipid peroxidative damages. In this study the physical and structural effects of carvedil ol an lipid bilayers are investigated by fluorescence techniques, diff erential scanning calorimetry and other physical methods. Carvedilol b inds to liposomal membranes (9:1 DMPC:DMPG) strongly with an apparent binding constant on the order of 10(4) M(-1) in PBS (pH 7.4). The char acteristic changes in its intrinsic fluorescence properties when bound to liposomes suggest that this compound is situated in a non-polar en vironment The Stern-Volmer and bimolecular quenching constants, determ ined using nitrate as the fluorescence quencher, for the free and boun d carvedilol indicate that the carbazole moiety is at a depth or >11 A ngstrom in the lipid bilayer. Fluorescence anisotropy measurements sho w that, unlike the membrane probes DPII and TMA-DPA, carvedilol is rel atively mobile, and does not have a rigidly-defined molecular orientat ion in the bilayers. Differential scanning calorimetry results indicat e that carvedilol is an effective membrane 'fluidizer' as it dose-depe ndently lowers the gel to liquid crystalline transition temperature an d broadens the endothermic transition. Comparative studies of interact ions of carbazole. 4 OH carbazole and carvedilol with the model liposo mal membranes reveal a possible role of membrane-partitioning in their antioxidant efficacy. These findings are discussed in perspective wit h the membrane biophysical properties of different classes of therapeu tic significant lipid antioxidants in mind.